The HIV-1 capsid is an important determinant of viral replication. Early studies demonstrated the intrinsic importance of the capsid in mediating uncoating of the viral core. More recently, the capsid has emerged as an important mediator of virus-host interactions. Cyclophilin A (CypA) is an abundant cellular protein known to bind the N-terminal domain of the capsid protein. CypA can promote infection of some HIV-1 strains in certain cells, but it can also inhibit infection. Despite many years of research, we still do not understand these mechanisms. I hypothesize that CypA modulates HIV-1 infection by regulating the interaction of specific cellular proteins with the HIV-1 capsid. Indeed, we have observed that CypA can regulate the non-human primate capsid-binding restriction factor, TRIM5?. However, the mechanism of this activity is poorly understood. I will determine the ability of CypA to regulate capsid-binding restriction factors by i) elucidating the mechanism of CypA-dependent TRIM5? restriction and ii) determining the ability of CypA to alter the capsid interactome using comparative proteomics.